[unreadable] [unreadable] Parkinson's disease (PD) involves pathological loss of neurons. The long-term objective of this research is to understand how environmental and genetic neurotoxic agents interact to signal and regulate the survival/apoptosis machinery in PD pathogenesis. Mitochondrial dysfunction has been proposed as a key mechanism that mediates demise of dopaminergic neurons in PD. However, the detailed molecular mechanisms by which PD relevant environmental toxicants affect mitochondria! transcription and activity remain unknown. Recently published findings from this lab highlight the key role of nuclear transcription factor myocyte enhancer factor 2 (MEF2) in neuronal survival. Unpublished studies have revealed unexpected presence and function of MEF2 in mitochondria. Based on this, this proposal seeks to explore the role of mitochondrial MEF2 in mediating and integrating the toxic signals of PD relevant environmental toxicants in the degeneration of dopamine neurons. The specific aims are to: 1). Determine the role of mitochondrial MEF2 in regulating transcription of mitochondrial genome in dopaminergic neurons; 2). Study the regulation of mitochondrial MEF2 by PD relevant environmental toxicants in mitochondrial dysfunction and neuronal death in cellular models; and 3). Establish the regulation and function of mitochondrial MEF2 in toxicant-induced animal models of PD. To accomplish Specific Aims 1-3 the role of MEF2 in mitochondrial gene transcription will be established in dopaminergic neuronal cell line SN4741 and primary neurons and a group of model toxicants including MPP+(metabolite of MPTP) and rotenone will be tested in cellular and rodent models to investigate whether de-regulation of mitochondrial MEF2 mediates the toxic effects of these toxins. Moreover, an attempt will be to extend these findings to PD patients by correlating the levels and activity of mitochondrial MEF2 with the disease. A combination of morphological, biochemical, functional and genetic methods will be employed in the proposed study. These studies will allow an assessment of whether or not targeting mitochondrial MEF2 underlies environmental toxicant-induced apoptosis of dopamine neurons. The novel insight gained from this study will demonstrate how environmental toxicants may disrupt mitochondrial function, providing a molecular explanation for the loss of dopamine neurons that may relevant to both sporadic and familial PD and a potential therapeutic target. [unreadable] [unreadable] [unreadable]